Schizophrenia Research Forum - A Catalyst for Creative Thinking

Mt. Sinai Cognition 2007—Cognitive Genomics

30 April 2007. The afternoon of Day 1 at the Mt. Sinai Conference featured the symposium "Cognitive Genomics, Cognitive Functioning, and Schizophrenia," organized by Robert Bilder and Tyrone Cannon, both of the University of California, Los Angeles.

In the first lecture, Anil Malhotra of Zucker Hillside Hospital, Glendale, New York, gave an "Introduction to Cognitive Genomics: From Single SNPs to Whole Genome Approaches." He illustrated the single nucleotide polymorphism (SNP) approach with the well-known studies of the polymorphism in codon 158 of the catechol-o-methyltransferase (COMT) gene that is presumed to result in higher or lower dopamine availability in prefrontal cortex. COMT genotype has been reported to be associated with alterations in cognitive function in both healthy subjects and those with schizophrenia (see SRF related news story).

He then described the strategy of drilling down from hypothesis-free genomewide linkage studies to SNPs and blocks of SNPs, or haplotypes, using the example of the dysbindin gene, DTNBP1 (Straub et al., 2002), located at chromosome 6p22.3. Linkage analysis had identified a chromosomal locus associated with IQ at 6p (Posthuma et al., 2005), which was also linked to cognitive dysfunction in a group of patients with schizophrenia (Hallmayer et al., 2005). Malhotra's group found that a specific haplotype in DTNBP1 was linked to schizophrenia risk (Funke et al., 2004) and to some measures of cognition in normal subjects (Burdick et al., 2006), and in subjects with schizophrenia (Burdick et al., 2007). As an example of how multiple genes can be combined in this approach, Malhotra noted that this decrement was only found in people with the valine/valine form of COMT.

Finally, Malhotra described the genomewide association study (GWAS), several of which have been reported in the past year and a half. He then focused on his own group's GWAS, which found an association between schizophrenia and two cytokine receptors (described in SRF related news story). Although the GWASs to date have used the disease phenotype, he predicted that studies using cognition as the phenotype would also be forthcoming.

Ty Cannon of the University of California, Los Angeles, in his talk entitled, " A Translational Genetics Approach to Schizophrenia: The Example of DISC1 and Memory-Related Endophenotypes," began with an overview of the contentious aspects of schizophrenia genetics. He ventured that the time has arrived to study schizophrenia endophenotypes in transgenic animal models, but he noted that not everyone would agree. While the glass-half-full camp points to well-replicated linkage data and association studies implicating biologically plausible genes in those regions (e.g., COMT, DTNBP1, NRG1, RGS4, DISC1, G72, DAAO, Akt1), the glass-half-empty camp, among them many geneticists, argue that functionally significant variants have not been identified and that the markers and haplotypes studied are not consistent across studies.

The identification of replicable causal variants has been difficult for a number of reasons, Cannon said, the first being the sheer complexity of the genetic architecture. Thus, studies powered to detect many genes, each of less than 10 percent effect, may be necessary. Furthermore, different genes (or, given that many of the current candidate genes are very large, different mutations of the same gene) may be at play in different families or gene pools. A third likely reason for the failure to find unimpeachable genes is that they are probably controlled by the environment; that is, they may remain silent unless environmental triggers expose them. Finally, he pointed out that different genes may impact different symptom domains, or dimensions, of the schizophrenia "syndrome,” a lead-in to his bigger message about the need to parse the syndrome and identify disease endophenotypes with homologues in mice.

Cannon presented an interesting model, using the structure of the various tributaries to a watershed, to conceptualize the contributions of both genes and environment to endophenotypes and the disease itself. Implicit in this model is the notion that certain critical endophenotypes or symptom domains—branch points "upstream" of the main disease river—should be a focus for translational genetics. The approach that Cannon proposed suggests that researchers link genes with validated schizophrenia endophenotypes and then evaluate homologous phenotypes in genetic mouse models. Rescue of such animal model phenotypes might then point the way to human therapies.

Cannon then turned his attention to DISC1 and his collaboration with the laboratory of Alcino Silva, also at UCLA. In work led by Weidong Li, they have shown that an inducible DISC1 fragment, when turned on in young mice but not adult mice, leads to behavioral abnormalities that may serve as models for schizophrenia endophenotypes, including working memory deficits and abnormalities in social behavior (see SRF related news story).

Robert Freedman of the University of Colorado reviewed the strategy that his group has employed to examine the effects of alterations in a gene—in this case CHRNA7, which codes for a subunit of the nicotinic acetylcholine receptor—on phenotypes ranging from gene expression through the diagnosis of schizophrenia itself. The pivotal work in this line of research was the Freedman group's work on the p50 auditory evoked potential, deficits in which initially helped to identify CHRNA7 as a disease candidate gene in the region of chromosome 15q4. A statistical association between variants in the promoter region of the gene and diminished p50 inhibition was found in controls and patients (Leonard et al., 2002).

How can this be linked to cognitive symptoms of schizophrenia? Both CHRNA7 variants and reduced p50 inhibition have been linked to impaired performance on neuropsychological tests of attention and other cognitive functions that have been reported to be impaired in schizophrenia. Finally, CHRNA7 variants have received some support in association studies.

Based on these and other data, Freedman's group has tried two therapeutic approaches. The first, nicotine, normalizes the p50 response but did not help to enhance cognition. More recently, the researchers have employed an α7 nicotinic receptor agonist—DMXB-A—that has weak activity at other nicotinic receptor subtypes. This drug also increases the p50 response in patients, and although patients report a qualitative improvement in symptoms, this is only weakly reflected in cognitive testing (see SRF related news story).

Terry Goldberg of Zucker Hillside Hospital then discussed the "Impact of Dopamine Regulating Genes on Cortical and Subcortical Information Processing: COMT and DAT1." In his work with the NIMH group, Goldberg and colleagues replicated the earlier work of Egan et al.—that met/met individuals outperform val/val subjects—on several memory and problem-solving paradigms. However, in more recent, larger samples of healthy volunteers, the results were somewhat different. While COMT genotype affected N-back, a test of simple working memory, the researchers were not able to replicate effects on the problem solving of the Wisconsin Card Sort Test (WCST). They did extend the findings into the area of attention, reporting that COMT variation affects simple target detection (continuous performance test and 0-back test).

In fMRI studies of brain regions involved in attentional control—cingulate cortex, dorsolateral prefrontal cortex (DLPFC), and parietal cortex—Goldberg and colleagues have also found an effect of COMT genotype. Normal subjects with val/val COMT showed greater activation in dorsal cingulate than those with met/met. This inefficiency of cortical processing is presumably traceable in part to less synaptic dopamine.

What happens if you increase dopamine signaling with tolcapone? Cognitively, this turned out to benefit those who are functioning with less dopamine (COMT val/val), Perhaps surprisingly, however, it did not negatively affect met/met COMT individuals, for whom the drug might have been expected to drop them out of the optimal range. There was a main effect of tolcapone (i.e., both groups improved) both in terms of activation of prefrontal cortex (PFC), and also on N-back, but on CANTAB-ID/ED, a computerized version of WCST, effects were mixed—in some cases m/m did worsen with tolcapone. Thus, COMT seems to have subtle but measurable effects on DA neurocognition in healthy controls.

Finally, the researchers extended their research to look at dopamine processing in the striatum, specifically the role of a polymorphism that alters expression of DAT1, the major determinant of striatal extracellular DA levels. The researchers designed a task that requires updating of information without a large working memory component, and found that this task activated the caudate nucleus on fMRI during the updating, but not "overwriting" of information.

Carol Tamminga, of the University of Texas Southwestern in Dallas, followed with a description of her research team's approach to "Cognitive Phenotyping Across the Schizophrenia-Bipolar Boundary." Citing the overlap in clinical features, endophenotypes, and major candidate genes for the two disorders (e.g., NRG1, DISC1, DAAO(G30)/G72), Tamminga and her colleagues suggest that endophenotyping strategies focusing on cognition may be useful in helping to categorize and understand psychotic disorders. To that end she presented the design, and some preliminary data, of a small study of psychotic disorders, with patients with schizophrenia or bipolar disorder and their family members.

Evidence for the overlap between the disorders is apparent even in basic clinical data from the groups in the study, where first-degree relatives of subjects with schizophrenia had a significantly increased risk of major depressive disorder. Tamminga then reviewed early data from cognitive tests that suggest that, whereas schizophrenia probands and their family members have deficits in some neuropsychological measures, as do subjects with bipolar disorder, this is not seen in family members of bipolar probands.

In the final talk of the Day 1 oral session, Robert Bilder used UCLA's Consortium for Neuropsychiatric Phenomics as an example of the integration of research approaches and disciplines in the service exploring "mechanistically relevant neurobehavioral phenotypes rather than conventional psychiatric syndromes," in particular informatics approaches to "cognitive phenomics" (see, e.g., Freimer and Sabatti, 2003), that serve both top-down approaches such as GWA of cognitive and neuropsychiatric phenotypes and bottom-up biological approaches.

Among the components of the consortium's approach to study endophenotypes of relevance to psychiatric disease are shared structures between different studies; e.g., human studies of cognition share the same study population of normal individuals and transgenic animal models are created to support these research aims.

In the service of this effort, the consortium is developing a number of Web-based bioinformatics tools, such as:

1. The Hypothesis Web —a knowledge management system.

2. PubGraph —a graphical display of scientific literature relationships.

3. PubBrain —an anatomical depiction of PubMed search terms.

These tools will be compatible with other systems, e.g., National Library of Medicine databases such as Online Mendelian Inheritance in Man (OMIM) and The Gene Ontology.—Hakon Heimer.

Comments on Related News


Related News: DISC1 Fragment Ties Schizophrenia-like Symptoms to Development in Mice

Comment by:  John Roder
Submitted 30 November 2007
Posted 30 November 2007

Some observations on the new report by Li and colleagues: this work is the first to map subregions of DISC1 and to show that a region that binds Nudel and LIS1 is important in generating schizophrenia-like perturbations in vivo. The authors express DISC1 C-terminus in mice, which interacts with Nudel and LIS1. They showed less native mouse DISC1 associations with Nudel mouse following gene induction. This suggests a dominant-negative mechanism.

No data was shown on native DISC1 levels following induction. Work from the Sawa lab shows that if murine DISC1 levels are reduced in non-engineered mice using RNAi, severe perturbations in development of nervous system are seen (Kamiya et al., 2005); however, behavior was not measured in this study. Severe perturbations would be expected based on the neonatal ventral hippocampal lesion model. In this latter model early brain lesions lead to later impairments in PPI and other behaviors consistent with schizophrenic-like behavior.

They use a promoter only expressed in the forebrain, so it is puzzling they see expression in the cerebellum. Expressed DISC1 bound to endogenous mouse Nudel and LIS1, presumably exerting a dominant-negative effect. Induction of the C-terminus DISC1 at day 7, but not in the adult, led to deficits in working memory, the forced swim test, and sociability. It would have been reassuring if these tasks were validated using antipsychotics and antidepressants. It is not clear in this study why the female C57 was used as a standard opponent mouse, and what genders of DISC1 mice have been used. Even though young C57 females (6 weeks old) were used as neutral partners, the data might be interpreted also as impaired sexual motivation in DISC1-Tg-Tm7 mice.

The authors made an attempt to translate their mouse data (low sociability) into a human population and found an association between DISC1 haplotypes and social impairments in a Finnish population (n = 232 samples), which supports a DISC1 role in social behavior, one of schizophrenia's symptoms. It would be useful to distinguish deficits in social interactions and impaired sexual behavior.

Deficits in working memory are also an important schizophrenia endophenotype, and it would be interesting to measure how specific the cognitive deficit is in DISC1-Tg-Tm-7 mice, estimating associative memory in classical fear conditioning, for example.

Induction of the transgene early in development to day 7 resulted in small changes in dendritic complexity in granule cells in the dentate gyrus. It is surprising larger changes were not observed. The role of DISC1 in the adult self-renewing progenitor cells in the dentate switches, so that DISC1 acts as a brake for dendritic complexity and migration (Duan et al., 2007). Thus, reductions in DISC1 in the adult dentate gyrus granule cells lead to enhanced dendrite growth/complexity.

In the adult, DISC1 was shown to interact with Nudel in controlling adult neurogenesis and development. It is of interest that in the Li et al. paper the transgene also perturbs native DISC1 binding to Nudel at day 7 but not adult. Synaptic transmission was reduced in CA1. It would have been nice to see a recording from dentate granule cells in which changes in dendritic complexity were found.

References:

Kamiya A, Kubo K, Tomoda T, Takaki M, Youn R, Ozeki Y, Sawamura N, Park U, Kudo C, Okawa M, Ross CA, Hatten ME, Nakajima K, Sawa A. A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol. 2005 Dec 1;7(12):1167-78. Abstract

Duan X, Chang JH, Ge S, Faulkner RL, Kim JY, Kitabatake Y, Liu XB, Yang CH, Jordan JD, Ma DK, Liu CY, Ganesan S, Cheng HJ, Ming GL, Lu B, Song H. Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell. 2007 Sep 21;130(6):1146-58. Abstract

View all comments by John Roder

Related News: DISC1 Fragment Ties Schizophrenia-like Symptoms to Development in Mice

Comment by:  Akira Sawa, SRF Advisor
Submitted 3 December 2007
Posted 3 December 2007

DISC1 may be a promising entry point to explore important disease pathways for schizophrenia and related mental conditions; thus, animal models that can provide us with insights into the pathways involving DISC1 may be helpful. In this sense, the new animal model reported by Li et al. (Silva and Cannon’s group at UCLA) has great significance in this field.

They made mice expressing a short domain of DISC1 that may block interaction of DISC1 with a set of protein interactors, including NUDEL/NDEL1 and LIS1. This approach, if the domain is much shorter, will be an important methodology in exploring the disease pathways based on protein interactions. Although the manuscript is excellent, and appropriate as the first report, the domain expressed in the transgenic mice can interact with more than 30-40 proteins, and the phenotypes that the authors observed might not be attributable to the disturbance of protein interactions of DISC1 and NUDEL or LIS1.

Now we have at least five different types of animal models for DISC1, all of which have unique advantages and disadvantages: 1) mice with a spontaneous mutation in an exon, which seem to lack some, but not all, DISC1 isoforms, from Gogos’s lab (see Koike et al., 2006; Ishizuka et al., 2007); 2) mice with mutations induced by a mutagen from Roder’s lab (Clapcote et al., 2007); 3) transgenic mice that express a dominant-negative mutant DISC1 from Sawa’s lab (Hikida et al., 2007); 4) transgenic mice that express a dominant-negative mutant DISC1 in an inducible manner from Pletkinov’s lab (Pletnikov et al., 2007); and 5) the mice from Silva’s and Cannon’s labs.

It is impossible to reach a firm conclusion on how the Scottish mutation of the DISC1 gene leads to molecular dysfunction until the data from autopsied brains of patients in the Scottish family become available. Millar and colleagues have published data of DISC1 in lymphoblastoid cells from the family members and propose an intriguing suggestion of how DISC1 is potentially disturbed in the pedigree (Millar et al., 2005); however, this remains in the realm of hypothesis/suggestion from peripheral cells. Thus, it is very important to compare the various types of DISC1 animal models in approaching how disturbance of DISC1 in brain leads to the pathophysiology of schizophrenia and related disorders.

References:

Koike H, Arguello PA, Kvajo M, Karayiorgou M, Gogos JA. Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice. Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3693-7. Abstract

Ishizuka K, Chen J, Taya S, Li W, Millar JK, Xu Y, Clapcote SJ, Hookway C, Morita M, Kamiya A, Tomoda T, Lipska BK, Roder JC, Pletnikov M, Porteous D, Silva AJ, Cannon TD, Kaibuchi K, Brandon NJ, Weinberger DR, Sawa A. Evidence that many of the DISC1 isoforms in C57BL/6J mice are also expressed in 129S6/SvEv mice. Mol Psychiatry. 2007 Oct ;12(10):897-9. Abstract

Clapcote SJ, Lipina TV, Millar JK, Mackie S, Christie S, Ogawa F, Lerch JP, Trimble K, Uchiyama M, Sakuraba Y, Kaneda H, Shiroishi T, Houslay MD, Henkelman RM, Sled JG, Gondo Y, Porteous DJ, Roder JC. Behavioral phenotypes of Disc1 missense mutations in mice. Neuron. 2007 May 3;54(3):387-402. Abstract

Hikida T, Jaaro-Peled H, Seshadri S, Oishi K, Hookway C, Kong S, Wu D, Xue R, Andradé M, Tankou S, Mori S, Gallagher M, Ishizuka K, Pletnikov M, Kida S, Sawa A. Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14501-6. Abstract

Pletnikov MV, Ayhan Y, Nikolskaia O, Xu Y, Ovanesov MV, Huang H, Mori S, Moran TH, Ross CA. Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia. Mol Psychiatry. 2007 Sep 11; Abstract

Millar JK, Pickard BS, Mackie S, James R, Christie S, Buchanan SR, Malloy MP, Chubb JE, Huston E, Baillie GS, Thomson PA, Hill EV, Brandon NJ, Rain JC, Camargo LM, Whiting PJ, Houslay MD, Blackwood DH, Muir WJ, Porteous DJ. DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science. 2005 Nov 18;310(5751):1187-91. Abstract

View all comments by Akira Sawa

Related News: DISC1 Fragment Ties Schizophrenia-like Symptoms to Development in Mice

Comment by:  David J. Porteous, SRF Advisor
Submitted 21 December 2007
Posted 22 December 2007

On the DISC1 bus
You wait ages for a bus, then a string of them come one behind the other. First, Koike et al. (2006) reported that the 129 strain of mouse had a small detection of the DISC1 gene and this was associated with a deficit on a learning task. The interpretation of this observation was somewhat complicated by the subsequent recognition that the majority, if not all, major DISC1 isoforms are unaffected by the deletion, but this needs further work (Ishizuka et al., 2007). Then, Clapcote et al. (2007) provided a very detailed characterization of two independent ENU-induced mouse missense mutations of DISC1, showing selective brain shrinkage and marked behavioral abnormalities that in one mutant were schizophrenia-like, the other more akin to mood disorder. Importantly, these phenotypes could be differentially rescued by antipsychotics or antidepressants. The main finger pointed to disruption of the interaction with PDE4 to misregulate cAMP signaling (Millar et al., 2005; Murdoch et al., 2007).

Then, back-to-back came two variants of DISC1 transgenic models from Johns Hopkins University (Pletnikov et al., 2007; Hikida et al., 2007) (see also SCZ Forum). Both Pletnikov and Hikida overexpressed a truncated form of DISC1 under the control of the CaMKII promoter (in Pletnikov’s case with an inducible CaMKU promoter). Both groups reported brain structural and behavioral abnormalities that aligned rather nicely with the earlier work of Clapcote et al. (2007). Pletnikov et al. showed that neurite outgrowth was attenuated in primary cortical neurons. They also showed that endogenous DISC1, LIS1, and SNAP25, but not NDEL1 or PSD-95, was reduced in mouse forebrain.

Now, Li et al. (2007) introduce yet another transgenic DISC1 model mouse, this time overexpressing a carboxy tail fragment of DISC1, so the opposite end of the DISC1 molecule from that overexpressed by Pletnikov and by Hikida. Intriguingly, Li et al. (as with all the preceding models) report significant behavioral differences for wild-type littermates. The point of added interest and significance here is that by using an inducible transgenic construct, they could elicit behavioral abnormalities if carboxy terminal DISC1 was expressed on postnatal day 7 only, but not in adult life. What are we to make of this and how do the models align? Li et al. interpret their results to suggest that DISC1 plays a crucial role, through NDEL1 and LIS1, in postnatal (but not adult) brain development. This study obviously raises some key questions. What is the developmental window of DISC1 effect? How can the lack of effect in the adult be reconciled with the rather striking effect on neurogenesis consequent upon downregulation of DISC1 in the adult mouse brain reported by Duan et al. (2007). And if overexpressing 5’ (Hikida, Pletnikov) or 3’ constructs (Li) can elicit similar phenotypes as seen in ENU-induced missense variants within exon 2 (Clapcote), can we come up with a unifying explanation? Perhaps not yet, but these various mouse models certainly emphasize the value of a multi-pronged mouse modeling approach. Combinations of “null,” transgenic, inducible, and missense mutants will help dissect the underlying processes. These studies also suggest that a variety of DISC1 variants in humans might elicit rather similar and also subtly different phenotypes. Indeed, Li et al. try to link their findings on the mouse to human studies, but here I feel there is cause for caution. The genetic association referred to maps to a haplotype in a quite distinct region of DISC1 and the direct or indirect functional effect of the haplotype is far from clear. It is, however, conceptually unlikely that this risk haplotype has a specific or restricted effect on Nudel and/or Lis1 binding. The corollary between a genetic association for a selected, but poorly defined sub-phenotype of schizophrenia with a poorly defined behavioral phenotype in the mouse may be a corollary too far too soon. Finally, whereas the focus of attention by Li, Pletnikov, and Hikida has been on the well-established/neurodevelopmental role of NDEL1 (and LIS1), the potential role of PDE4B both in neurosignaling (related to behavior, learning, and memory) and possibly also neurodevelopment should not be overlooked. In this regard it is noteworthy that PDE4 interacts both with the head and the carboxy tail domain of DISC1 (Hannah et al., 2007) and this most likely contributes to the phenotype in all the models described to date.

References:

Clapcote SJ, Lipina TV, Millar JK, Mackie S, Christie S, Ogawa F, Lerch JP, Trimble K, Uchiyama M, Sakuraba Y, Kaneda H, Shiroishi T, Houslay MD, Henkelman RM, Sled JG, Gondo Y, Porteous DJ, Roder JC. Behavioral phenotypes of Disc1 missense mutations in mice. Neuron. 2007 May 3;54(3):387-402. Abstract

Hikida T, Jaaro-Peled H, Seshadri S, Oishi K, Hookway C, Kong S, Wu D, Xue R, Andradé M, Tankou S, Mori S, Gallagher M, Ishizuka K, Pletnikov M, Kida S, Sawa A. Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14501-6. Abstract

Ishizuka K, Chen J, Taya S, Li W, Millar JK, Xu Y, Clapcote SJ, Hookway C, Morita M, Kamiya A, Tomoda T, Lipska BK, Roder JC, Pletnikov M, Porteous D, Silva AJ, Cannon TD, Kaibuchi K, Brandon NJ, Weinberger DR, Sawa A. Evidence that many of the DISC1 isoforms in C57BL/6J mice are also expressed in 129S6/SvEv mice. Mol Psychiatry. 2007 Oct 1;12(10):897-9. Abstract

Koike H, Arguello PA, Kvajo M, Karayiorgou M, Gogos JA. Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice. Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3693-7. Abstract

Li W, Zhou Y, Jentsch JD, Brown RA, Tian X, Ehninger D, Hennah W, Peltonen L, Lönnqvist J, Huttunen MO, Kaprio J, Trachtenberg JT, Silva AJ, Cannon TD. Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice. Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18280-5. Abstract

Millar JK, James R, Christie S, Porteous DJ. Disrupted in schizophrenia 1 (DISC1): subcellular targeting and induction of ring mitochondria. Mol Cell Neurosci. 2005 Dec 1;30(4):477-84. Abstract

Duan X, Chang JH, Ge S, Faulkner RL, Kim JY, Kitabatake Y, Liu XB, Yang CH, Jordan JD, Ma DK, Liu CY, Ganesan S, Cheng HJ, Ming GL, Lu B, Song H. Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell. 2007 Sep 21;130(6):1146-58. Abstract

Murdoch H, Mackie S, Collins DM, Hill EV, Bolger GB, Klussmann E, Porteous DJ, Millar JK, Houslay MD. Isoform-selective susceptibility of DISC1/phosphodiesterase-4 complexes to dissociation by elevated intracellular cAMP levels. J Neurosci. 2007 Aug 29;27(35):9513-24. Abstract

Pletnikov MV, Ayhan Y, Nikolskaia O, Xu Y, Ovanesov MV, Huang H, Mori S, Moran TH, Ross CA. Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia. Mol Psychiatry. 2007 Sep 11; [Epub ahead of print] Abstract

View all comments by David J. Porteous

Related News: New Schizophrenia Drug Studies Offer Threads of Hope

Comment by:  John Michael Brummer
Submitted 6 September 2008
Posted 6 September 2008
  I recommend the Primary Papers

Related News: MTHFR, COMT Genes Work Together to Bring Down Cortical Activation in Schizophrenia

Comment by:  Jennifer Barnett (Disclosure)
Submitted 19 December 2008
Posted 19 December 2008

The recent studies of Prata and colleagues and Roffman and colleagues shed considerable further light on the ongoing mysteries of the catechol-O-methyltransferase Val158Met polymorphism and its effects on the proposed “inverted-U” shape of cortical dopamine function. Both study teams should be congratulated on these high-quality studies using what are, for neuroimaging experiments, impressive numbers of both patients and controls.

Our understanding of the effects of the COMT Val/Met polymorphism in humans remains incomplete despite no shortage of elegant studies and intriguing results. In their landmark 2001 paper, Egan and colleagues reported that Val carriers showed poorer cognitive function, a higher risk for schizophrenia, and reduced prefrontal efficiency when compared with Met carriers. These associations, along with a multitude of other psychological and psychiatric phenotypes, have since been tested in labs across the world. Meta-analyses of the available data have concluded that there is little influence of the Val/Met polymorphism on risk for schizophrenia (Allen et al., 2008; Fan et al., 2005; Munafo et al., 2005) or cognitive function (Barnett et al., 2008). Perhaps because of the increased cost and difficulty of collecting imaging data compared with cognitive or disease status, rather fewer studies have been published testing the hypothesis that Val/Met affects prefrontal cortical efficiency, but those few (e.g., Ho et al., 2005) do appear consistent with the original report .

Prata et al. (2008) studied the effects of Val/Met on cortical activation during a verbal fluency task and report an interesting, if somewhat unintuitive result: that there are opposite effects of genotype on task performance and cortical activation in patients with schizophrenia, compared with those seen in healthy controls. In patients, Val alleles were associated with poorer task performance, while in controls, there was no significant difference between genotype groups. The trend, however, was for better task performance among Val-carrying controls, and the group x genotype interaction term was significant. These results were interestingly reflected in regional activation patterns, where in the right peri-Sylvian region Val alleles were associated with increased activation in patients, and decreased activation in controls. Further analyses suggested that these group x genotype interactions may partly reflect genetically driven differences in functional connectivity. Explanations for these opposite effects in patients and controls are consistent with an inverted-U shape of dopaminergic function where patients lie on the left-hand side of the U (suboptimal dopamine) and controls lie somewhat to the right of the center, such that increased cortical dopamine (as experienced by Met carriers) is slightly disadvantageous. Interestingly, we found the same pattern when comparing the effect of Val/Met genotype on N-back performance in patients and controls (Barnett et al., 2008); it is good to see these non-linear behavioral results supported by structural and functional imaging data.

The Val/Met polymorphism is certainly not the only determinant of COMT function, and we now know that other SNPs within the gene greatly affect the amount of COMT expressed (Nackley et al., 2006). Moreover, in affecting cortical dopamine and norepinephrine, COMT does not operate alone. Roffman and colleagues’ study (Roffman et al., 2008) very nicely demonstrates how much we have still to learn about potential gene-gene interaction (epistatic) effects. They studied brain activation during a working memory task and analyzed the combined effects of Val/Met and a functional polymorphism in MTHFR, a gene with plausible biological interactions with COMT. In this study, COMT genotype alone did not predict variation in activation in dorsolateral prefrontal cortex. There was a three-way interaction, however, between COMT and MTHFR genotypes and diagnostic group, such that MTHFR genotype appeared to modulate prefrontal activation most in Val/Val patients (who would be expected to have the lowest prefrontal dopamine), and among Met/Met controls (who would be expected to have the highest prefrontal dopamine, potentially putting them beyond the optimal level in the inverted-U model).

Despite considerable interest in gene-gene and gene-environment interactions among schizophrenia researchers, replications of such interactions have been relatively few and far between. While it is notoriously difficult to demonstrate biological interaction from statistical data alone, Roffman’s study provides us with hope that a really good hypothesis may still give us reason to try and do so.

References:

Allen NC, Bagade S, McQueen MB, Ioannidis JP, Kavvoura FK, Khoury MJ, Tanzi RE, Bertram L. Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet. 2008 Jul 1;40(7):827-34. Abstract

Barnett JH, Scoriels L, Munafň MR. Meta-analysis of the cognitive effects of the catechol-O-methyltransferase gene Val158/108Met polymorphism. Biol Psychiatry. 2008 Jul 15;64(2):137-44. Abstract

Fan JB, Zhang CS, Gu NF, Li XW, Sun WW, Wang HY, Feng GY, St Clair D, He L. Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis. Biol Psychiatry. 2005 Jan 15;57(2):139-44. Abstract

Ho BC, Wassink TH, O'Leary DS, Sheffield VC, Andreasen NC. Catechol-O-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow. Mol Psychiatry. 2005 Mar 1;10(3):229, 287-98. Abstract

Munafň MR, Bowes L, Clark TG, Flint J. Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case-control studies. Mol Psychiatry. 2005 Aug 1;10(8):765-70. Abstract

Nackley AG, Shabalina SA, Tchivileva IE, Satterfield K, Korchynskyi O, Makarov SS, Maixner W, Diatchenko L. Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science. 2006 Dec 22;314(5807):1930-3. Abstract

Prata DP, Mechelli A, Fu CH, Picchioni M, Kane F, Kalidindi S, McDonald C, Howes O, Kravariti E, Demjaha A, Toulopoulou T, Diforti M, Murray RM, Collier DA, McGuire PK. Opposite Effects of Catechol-O-Methyltransferase Val158Met on Cortical Function in Healthy Subjects and Patients with Schizophrenia. Biol Psychiatry. 2008 Dec 1; Abstract

Roffman JL, Gollub RL, Calhoun VD, Wassink TH, Weiss AP, Ho BC, White T, Clark VP, Fries J, Andreasen NC, Goff DC, Manoach DS. MTHFR 677C --> T genotype disrupts prefrontal function in schizophrenia through an interaction with COMT 158Val --> Met. Proc Natl Acad Sci U S A. 2008 Nov 11;105(45):17573-8. Abstract

View all comments by Jennifer Barnett

Related News: MTHFR, COMT Genes Work Together to Bring Down Cortical Activation in Schizophrenia

Comment by:  S.H. Lin
Submitted 15 January 2009
Posted 19 January 2009
  I recommend the Primary Papers

The “inverted-U” shape of cortical dopamine function with regard to the COMT Val158Met polymorphism is an interesting issue worthy of discussion. The COMT enzyme may modulate the balance of tonic and phasic dopamine function depending on the area-specific neurochemical environment (Bilder et al., 2004). There is thought to be a complex nonlinear relationship between dopamine availability and brain function (Williams et al., 2007).

Our study (Liao et al., 2008) examined the relationships of three COMT SNPs—rs737865 in intro 1, rs4680 in exon 4 (Val158Met), and downstream rs165599—to schizophrenia and its related deficits in neurocognitive function in families of patients with schizophrenia in Taiwan. The study results indicated that the Val allele was associated with better performance on the WCST (i.e., greater Categories Achieved and Conceptual Level Response and fewer Perseverative Errors) or CPT (i.e., greater d'), which might be explained by an “inverted U” shaped relationship between dopamine levels and prefrontal cortex function (Cools and Robbins 2004; Mattay et al., 2003). This model reveals that an optimal functioning occurs within a narrow range of dopamine level, and both excessive and insufficient dopamine levels impair working memory performance. Our results indicate that the genetic variants in COMT might be involved in modulation of neurocognitive functions, hence conferring increased risk to schizophrenia.

References:

Bilder, R.M., Volavka, J., Lachman, H.M. & Grace, A.A. (2004) The catechol-O-methyltransferase polymorphism: relations to the tonic-phasic dopamine hypothesis and neuropsychiatric pheno-types. Neuropsychopharmacology 29, 1943–1961. Abstract

Cools, R. and Robbins, T.W. (2004) Chemistry of the adaptive mind. Philos Transact A Math Phys Eng Sci 362, 2871–2888. Abstract

Liao S.Y., Lin S.H., Liu C.M., Hsieh M.H., Hwang T.J., Liu S.K., Guo S.C., Hwu, H.G., Chen W.J. (2008): Genetic variants in COMT and neurocognitive impairment in families of patients with schizophrenia. Genes, Brain and Behavior. Abstract

Mattay, V.S., Goldberg, T.E., Fera, F., Hariri, A.R., Tessitore, A., Egan, M.F., Kolachana, B., Callicott, J.H. and Weinberger, D.R. (2003) Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci USA 100, 6186–6191. Abstract

Williams, H.J., Owen, M.J. and O‘Donovan, M.C. (2007) Is COMT a susceptibility gene for schizophrenia? Schizophr Bull 33, 635–641. Abstract

View all comments by S.H. Lin